(1) An endothelin is a strong vasoconstrictive peptide derived from endotheliocytes, which consists of 21 amino acids, and was isolated and identified by Yanagisawa et al in 1988 [M. Yanagisawa et al., Nature 332, 411 (1988)]. The vasoconstriction by endothelin is stronger than that by known vasoconstrictive substances such as angiotensin II, vasopressin and neuropeptide Y. Although the constriction is moderate, it lasts for a long time. Endothelin also shows contractive action on various blood vessels inclusive of microvessels of various animals.
The contraction by endothelin is not affected by receptor antagonists and synthesis inhibitors of known blood vessel agonists, such as norepinephrine, histamine, acetylcholine, serotonin, leukotriene and thromboxane A.sub.2, and is known to be only suppressed by potential-dependent calcium channel antagonists and endotheline receptor antagonistic substances.
It is also known that endothelin induces not only vasoconstriction, but also strong airway stenosis [Y. Uchida et al., Eur. J. Pharmacol. 154, 227 (1988)]. It has been gradually clarified that endothelin has various physiological actions such as promotion of release of atrial sodium diuretic hormone in cultured atrial muscle of rats and suppression of renin secretion in pararenal glomerular cells.
Although its action in the living body and pathological involvement have not been entirely elucidated, endothelin is considered to be involved in various diseases, in view f the wide distribution of endothelin receptors and a variety of actions it shows. In fact, the involvement of endothelin has been pointed out in various diseases and experimental animal models. To be specific, patients and pathological animal models with pulmonary hypertension [D. J. Stewart et. al., Am. Col. Physic. 114, 464 (1991)], renal failure [M. Shichiri et al., Hypertension 15, 493 (1990)], heart failure [K. B. Margulies, Circulation 82, 2226 (1990)], angina pectoris [T. Toyo-oka et al., Circulation 83, 476 (1991)], myocardial infarction [Lancet Jul. 1, 53 (1989)], ischemic brain, peripheral diseases, arteriosclerosis, romsoongitis obliterans (Bueger's disease), aortitis syndrome (Takayasu's disease) [JAMA, 264, 2868 (1990)] or bronchial asthma show increased endothelin level in plasma, thus suggesting the possibility of endothelin being deeply involved in the onset and cause, retention and progress of the diseases.
(2) A cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are tntracellular second messengers, are decomposed and inactivated by phosphodiesterase (PDE). It has been known that PDE is widely distributed in the tissues in the body, and that PDE inhibitors provide various pharmacological actions by increasing cAMP and cGMP levels in the cells by inhibiting PDE. For example, they provide relaxing action in vascular smooth muscles and tracheal smooth muscles, as well as positive inotropic action and chronotropic action in the heart. They also control the central nervous function caused by increased cAMP in the central nervous system; namely, they show antidepression and memory learning function-improving action. Besides these, they show blood platelets coagulation-suppressive action, suppressive action on the activation of inflammatory cells, and lipolytic action in fat tissues [C. D. Nicholson et al., Trends in Pharmacol. Sci., 12, 19 (1991)].
Accordingly, the provision of, (1) a compound effective for the prophylaxis and treatment of various circulatory diseases and respiratory diseases such as hypertension, renal failure, heart failure, angina pectoris, myocardial infarction, ischemic brain-peripheral diseases, arteriosclerosis, romsoongiitis obliterans, aortitis syndrome and bronchial asthma, which are caused by abnormal regulation of various biological actions mediated by endothelin, a kind of autacoid produced in the body, by suppressing such physiological actions, and (2) a compound effective as a therapeutic agent for various diseases such as heart failure, thrombosis, depression, degradation of central nervous function after cerebrovascular obliteration, cerebrovascular dementia, senile dementia, Alzheimer dementia, bronchial asthma, various inflammations and obesity, which suppresses PDE, have been desired.